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Enantiomeric deoxycholic acid: total synthesis, characterization, and preliminary toxicity toward colon cancer cell
Bryson W Katona1, Nigam P Rath, Shrikant Anant
1Department of Molecular Biology and Pharmacology, Division of Gastroenterology, Washington University in St Louis School of Medicine, St Louis, MO 63110, USA.
Abstract:
Deoxycholic acid (DCA) is an endogenous secondary bile acid implicated in numerous pathological conditions including colon cancer formation and progression and cholestatic liver disease. DCA involvement in these disease processes results partly from its ability to modulate signaling cascades within the cell, presumably through both direct receptor activation and general detergent mediated membrane changes. To further explore DCA induced changes in cell signaling, we completed a total synthesis of enantiomeric deoxycholic acid (ent-DCA) from achiral 2-methyl-1,3-cyclopentanedione. Using a modified method of the synthesis of ent-testosterone that proceeds through the (R)-(-)-Hajos-Parrish ketone, we have completed the successful synthesis of ent-DCA in 25 steps with a yield of 0.3% with all stereochemical assignments of the product confirmed by X-ray crystallography. Our studies toward this synthesis also uncovered the methodology for the development of a novel A,B-cis steroidal skeleton system containing a C3-C9 single bond as well as conditions to selectively ketalize the typically less reactive 12-carbonyl in poly-keto A,B-cis androgens. The critical micelle concentration (cmc) of ent-DCA, determined by a dye solubilization method, was identical to the cmc of natural DCA. Toxicity studies toward HT-29 and HCT-116 human colon cancer cell lines demonstrated that ent-DCA had similar effects on proliferation, yet showed a markedly decreased ability to induce apoptosis as compared to natural DCA.
Insights
Researchers synthesized enantiomeric deoxycholic acid (ent-DCA) to study its effects on colon cancer cells. While ent-DCA showed similar proliferation effects to deoxycholic acid (DCA), it induced significantly less apoptosis, offering new insights into bile acid roles in cancer.
Area of Science:
- Biochemistry
- Organic Chemistry
- Cancer Biology
Background:
- Deoxycholic acid (DCA) is an endogenous bile acid linked to colon cancer and liver disease.
- DCA influences cell signaling through receptor activation and membrane changes.
- Understanding DCA's role requires studying its stereoisomers.
Purpose of the Study:
- To synthesize enantiomeric deoxycholic acid (ent-DCA).
- To investigate the biological effects of ent-DCA compared to natural DCA.
- To explore novel synthetic methodologies for steroidal compounds.
Main Methods:
- Total synthesis of ent-DCA from achiral 2-methyl-1,3-cyclopentanedione.
- Utilized a modified synthesis of ent-testosterone via the (R)-(-)-Hajos-Parrish ketone.
- Confirmed stereochemistry using X-ray crystallography and determined critical micelle concentration (cmc).
- Assessed toxicity and apoptosis induction in HT-29 and HCT-116 colon cancer cell lines.
Main Results:
- Successfully synthesized ent-DCA in 25 steps with a 0.3% yield.
- Developed a novel synthetic route for A,B-cis steroidal skeletons and selective ketalization.
- ent-DCA exhibited identical cmc to natural DCA.
- ent-DCA showed similar proliferation effects but markedly reduced apoptosis induction in colon cancer cells compared to DCA.
Conclusions:
- The synthesis of ent-DCA provides a tool to study bile acid stereochemistry and function.
- ent-DCA's reduced ability to induce apoptosis suggests stereospecific mechanisms in DCA-related colon cancer progression.
- Novel synthetic strategies were established for complex steroidal structures.
